Download Partial androgen insensitivity syndrome. Multidisciplinary approach

Rom J Leg Med [21] 201-206 [2013]
DOI: 10.4323/rjlm.2013.201
© 2013 Romanian Society of Legal Medicine Partial androgen insensitivity syndrome. Multidisciplinary approach
- genetic, endocrinological, surgical, psychological, psychiatric, social,
ethical and forensic
Radu Spătaru1,*, Gabriela Costea2, Luminita Spiridon2, Camelia Procopiuc3, Niculina Dumitriu1,
Dana-Georgeta Sîrbu2, Adrian Sîrbu2, Monica Ivanov1, Iozsa Dan1
_________________________________________________________________________________________
Abstract: The partial androgen insensitivity syndrome is a particular form of sexual ambiguity. In these cases, accurately
assigning the legal gender at birth has major repercussions on all aspects of the ontogenic personality development. The surgical
treatment is differentiated by phenotypic appearance, sexual identity and legal gender; furthermore, the surgical therapeutic
decision depends on the outcome of clinical/ psychiatric and psychological assessments; thus, a multidisciplinary approach of
these cases is required.
Key Words: androgen insensitivity syndrome, Reifenstein syndrome, severe hypospadias, sexual identity, passive
aggression.
A
ndrogenic hormones exert their effect on the
differentiation and development of the normal
male phenotype through a protein called the androgen
receptor (AR) [1], located on the long arm of chromosome
X (Xq11-12) [2]. The androgen insensitivity syndrome is
defined by impaired sexual development in individuals with
genetic male sex due to lack of response of the target organs to
androgen stimulation; it is the result of inactivating mutations
in the AR gene X-linked recessive transmitted, which cause
varying degrees of insensitivity of the androgen receptor.
Phenotypically, androgen insensitivity can be classified in:
full insensitivity to androgens (CAIS - Complete androgen
insensitivity syndrome); partial insensitivity to androgens
(PAIS - Partial androgen insensitivity syndrome), and
minimal insensitivity to androgens (MAIS - mild androgen
insensitivity syndrome) [3].
The occurrence of the androgen insensitivity
syndrome has been assessed based on studies of small
populations [4]. Thus, the CAIS is estimated to occur in 1
out of 20.400 boys born [5], while the occurrence of PAIS
has been estimated in 1 out of 130.00 boys born [6]. Within
the PAIS several phenotypes have been identified: female
phenotype (feminine EG, female-like pubic pilosity, with
or without clitorimegaly and partially or totally merged
labia), genital ambiguity, predominantly male phenotype
- Reifenstein syndrome - with micropenis, perineal
hypospadias and cryptorchidism [7]. The diagnosis is
confirmed through laboratory hormone tests, which show
elevated levels of serum testosterone, luteinizing hormone
(LH), FSH, as well as through genetic testing, which show
male karyotype - 46XY. The diagnosis and treatment of these
patients require a multidisciplinary approach. The surgical
1) "M.S. Curie" Emergency Clinical Children's Hospital
* Corresponding author: PhD, MD, Pediatric Surgery Clinic of the "M.S. Curie" Emergency Clinical Children's
Hospital, 20 Constantin Brîncoveanu Blvd. 4th District, Bucharest, E-mail: [email protected]
2) "Mina Minovici" National Institute of Forensic Medicine
3) "C.I. Parhon” National Endocrinology Institute Bucharest, Department of Pediatric Endocrinology
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Spătaru R. et al
Partial androgen insensitivity syndrome. Multidisciplinary approach
treatment aims for the surgical correction of the EG in order
to obtain a phenotypically male (most of the times) or female
aspect. The surgical treatment is regarded as a challenge
because of the technical difficulties both in correcting the
scrotal hypospadias and in regards to the vaginoplasty.
Patients with intersexuality have psychological and
social difficulties caused at least in part by parental attitudes
and behavior, which is why long-term psychological
counseling is recommended for both parents and children;
it should start the moment the diagnosis was established
[8]. Early diagnosis, followed by a timely start of treatment,
plays a crucial role both in obtaining long-term good results
and prevention through genetic counseling.
comes for a consult), legal gender as female, reduced
facial and body pilosity, axillary pilosity present, triangular
pubic pilosity Tanner stage III, well-defined muscles,
gynecomastia - mammary glands stage B III / IV Tanner
- bilateral cryptorchidism (observed clinically and via the
ultrasound), scrotal hypospadias with a clitoral penile aspect
(Figs. 3 and 4). Genetic determination: test Barr negative,
karyotype: 46 XY.
The hormonal investigation, perfomed as a
collaboration between the "M.S Curie" Emergency Clinical
Children's Hospital and the Parhon Institute from Bucharest,
is presented in table 1 for both patients.
Taking into consideration the karyotype, the
hormonal investigation results and the clinical examination,
OBJECTIVES AND METHOD
both patients were diagnosed with the syndrome of partial
insensitivity to androgen action - the Reifenstein syndrome.
Case study
The surgical procedures in patient "M" consisted of:
Case ”M”: clinical evaluation: 17-year-old patient, bilateral orchiopexy; mammary gland ablation; multistage
legal gender as male, 155 cm waist (-3.1 DS), weight = treatment of the scrotal hypospadias (Stage I of flexing and
48 Kg, genetic target waist: 174 cm (-0.43 DS), reduced transforming the scrotal hypospadias in proximal penile
facial and body pilosity, axillary pilosity present, triangular hypospadias, stage II: urethroplasty with bringing the
pubic pilosity Tanner stage III, well-defined muscles, urethral meatus at the glandular level)(Figs. 5-7).
gynecomastia - mammary glands stage B III / IV Tanner In the "F" case study, due to the fact that the patient
- bilateral cryptorchidism (both testicles present in the came to the doctor late (22-year-old), there was a mismatch
inguinal canal, as observed clinically and via the ultrasound) between genetic sex (male) and legal sex (female), and
and scrotal hypospadias with a clitoral aspect of the penis the patient had expressed her wish to do so, the surgery
(Figs. 1 and 2). The bone age X-ray shows almost fused consisted initially of gonads removal, later to be followed-up
growth plates. Genetic determination: Barr test negative, with a reduction plasty of the clitoris and vaginoplasty. The
karyotype: 46 XY.
anatomical and pathological investigation of the surgically
Case ”F”: 22-year-old patient (the first time she removed gonads revealed no malignant transformation.
The psychiatric examination was carried out within
the Forensic Psychiatry Department of the "Mina Minovici" National Forensic
Institute in Bucharest (semistructured interviews with
semi-open and open ended
questions were used):
1. The heredo-collateral
history is presented in Figure
Figure 1. Initial status: scrotal hypospadias Figure 2. Gynecomastia - mammary glands 8.
with significant flexion of the penis (clitoral stage III/IV Tanner.
2. Personal history.
aspect).
The first sibling was
declared a girl at birth; the
second born was declared
a boy. The two patients
denied a pathologically
relevant personal history.
3. Premorbid personality.
Patients come from rural
areas. The family presents
with genetic pathology, has
low social, economic and
educational levels, adheres
Figure 3 and 4. Scrotal hypospadias with a clitoral penile aspect.
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Table 1. Hormonal investigations
Hormones
Luteinizing Hormone (LH)
FSH
Serum Testosterone
Serum Estradiol
Sex hormone binding globulin (SHBG)
Anti-Müllerian hormone (AMH)
Serum Dihydrotestosterone
17 oh progesterone
Serum Androstenedione
DHEAS
Total HCG
Patient ”M”
Results
Reference value
13.94 mIU/mL
1.7 – 8.6 mIU/mL
17.46 mIU/mL
1.5 – 12.4 mIU/mL
13.75 ng/mL
1.75 – 7.81 ng/mL
44.44 pg/mL
La bărbat < 20 pg/mL
80.69 nmol/L
14.5 – 48.4 nmol/L
4.44 ng/mL
1.3 – 14.8 ng/mL
0.753 ng/mL
0.25 – 0.99 ng/mL
2.4 ng/mL
0.3 – 3 ng/mL
2.81 ng/mL
0.91 – 4 ng/mL
297.1 mcg/dL
70.2 – 492 mcg/mL
-
Figure 5. Urethroplasty stage I – immediate post-operative
status. (transforming the scrotal hypospadias in proximal
penile hypospadias and penile deflection).
Figure 6. Urethroplasty stage II using surrounding ventral
penile skin, preoperative status.
Figure 7. Urethroplasty stage II using surrounding ventral
penile skin. Post-operative status.
Results
24.3 mUI/mL
35.4 mUI/mL
51.63 nmol/L
181.3 pmol/L
76.32nmol/L
958 pg/mL
4.27ng/mL
<0.1 mUI/mL
Patient”F”
Reference value
1.7 – 8.6 mUI/mL
1.5 – 12.4 mUI/mL
0.22 – 2.9 nmol/L
28 – 156 pmol/L
14.5 – 48.4nmol/L
250 – 999pg/mL
0.1 – 2.99 ng/mL
< 2.6 mUI/mL
to ancestral values which are inconsistent with the macro
environment it is part of; it is marginalized without being
ostracized. The family has shown indifference towards
the children's pathology so far. Parental attitude towards
children's school education is negative. ("M" - 4 years of
primary school, "F" - 3 years). The educational model shows
a clear ancestral delineation between the different social roles
of men and women - a model the patients have acquired as
well. They admit sporadic conflicts with the parents related
to their pathology. Each patient presents with a sexual
orientation toward the opposite sex of their legal gender.
4. Current psychiatric status. Both patients have
a common psychiatric chart with different characteristics.
The differences are shown in table 2 (with reference to the
results of hormonal tests). What they have in common can
be summarized as follows: lack of psychiatric symptoms
of intensity/ clinical relevance; cognitive level in the
lower intelligence spectrum; mismatch between logical
and reasoning ability performance, the ability to associate,
compare and grasp the absurd, above the presumed level;
low level of acquired abstract concepts; grammatical
discourse above the presumed level; slightly impaired
verbal fluency; acquisition of practical information and
skills related to mechanical mechanisms, modern ones
included, "F" being more adept in this regard; affective
deprivation; compensation mechanisms by avoiding the
home; harsh analysis of their circumstances; life plans
are unrealistic; expectations about their future are linked
with the success of the surgeries; they identify with their
legal gender. A psychiatric diagnostic cannot be delimited
based on the ICD - 10 criteria; clinically, it is estimated that
"M" presents with a risk of personality structuring on the
"borderline" model, while with "F" one can raise the issue of
reactive, primitive behaviors, based on the noted structure.
5. Psychological examination (psychological
interview, projective tests). In both patients the results were
interpreted as expressing the primitive I, a projection of
"monstrosity" awareness, hidden aggression, repressed
depression, anxiety, efforts to adapt, shallow and ineffective
real adjustment, severe risk of violent, explosive behavior;
with "M" typical borderline traits stand out, while with "F",
paranoid type ones.
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Partial androgen insensitivity syndrome. Multidisciplinary approach
Figure 8. The heredo-collateral history.
Table 2. Psychiatric examination – differences between „M” and „F”
Investigated aspect
Testosterone, luteinizing hormone, follicle stimulating hormone (fsh)
Sex hormone binding globulin (shbg)
Estradiol
Masculine-type build
Deficient chronological ascertainments, verbal disinhibition
Masculine aspects in childhood
Sensitivity – interpretability – paranoid aspects
Instability, habitual impulsivity
Anger build-up, explosive violent reactions
Sublimation by masking the feelings
Elaborate reasoning to explain behaviour
Different sublimation, according to rigid education - In accordance with legal gender Passive aggression with anger build-up
M
X
X
XX
X
X
X
X
XX
X
XX
X
X
F
XX
X
X
XX
XX
XX
XX
X
XX
X
X
XX
XX
legend: „x” = yes; „xx” = yes with a higher level / more in one of the two patients.
DISCUSSIONS AND CONCLUSIONS
Given the observed phenotypic traits, we consider
both patients fall under the PAIS severity level number 3
according to the androgen insensitivity severity scale (Fig. 9)
[after 9].
1. From the medical point of view, the only
therapeutical solution is the surgical one, which consists in
correcting the EG towards either the male or the female sex,
depending on the severity of androgen insensitivity.
Figure 9. Rejender Androgen insensitivity severity scale [9].
204
In the "M" case study, it was intended to treat the
gynecomastia, the orchiopexy and the hypospadias. The
correction of the severe scrotal hypospadias requires a
multistage approach. The penile deflection requires the use
of penile foreskin to cover the ventral penile skin defect.
On the other hand, the neourethra can be obtained from
surrounding skin. If this is insufficient, one can use either
dorsal foreskin flap or oral cavity (Bracka procedure) [10,
11]. For "M", the urethroplasty was performed in 2 surgical
stages, using the urethral plate (stage 1) and ventral penile
skin (stage two) with good results. Given the known risk
of developing testicular germ tumors - 15% - if the gonad
is positioned nonscrotally [12], it was recommended a
periodic ultrasound monitoring once the testicles descended
into the scrotum. Betha HCG and alpha-fetoprotein will
also be checked regularly.
Patient "F" (which came to the doctor for the first
time at the age of 22) has expressed her desire to maintain
her legal gender. The gonad ablation was performed, later
to be followed-up with a reduction plasty of the clitoris and
vaginoplasty.
All types of androgen insensitivity are associated
with infertility, with some exceptions for partial or moderate
forms [13], as well as sexual dysfunction (impotence and
lack of ejaculation)[14].
1. From a multidisciplinary/ interdisciplinary
perspective, PAIS was approached through a trivalent
Romanian Journal of Legal Medicine Vol. XXI, No 3(2013)
Table 3. Integrated / interdisciplinary medical synthesis (trivalent cybernetic model)
ARGUMENTATION BY CLINICAL REASONING
TRUE
POSSIBLE
FALSE
 Genetic defect and incorrectable hormonal disorders; infertility;
 Unsupportive family, severe instructive – educational deficit, inadequate parental model, poor social,
economic and cultural status;
 Sublimation with poor coping mechanisms, social marginalization;
 Passive/ dormant aggressiveness;
 Biological, psychological and social vulnerability;
 Successful surgical corrections – the only beneficial somatic, psychological and social factor
 Manifest aggressive behaviour, addictions, suicide, forensic implications;
 Failure of complex medical monitoring, due to lack of compliancy;
 Malign transformation – testicular germ tumors
 Completely normal sex life
cybernetic model (true - false - possible), specifying
vulnerabilities at all levels of personality structure
(biological, psychological, sociological).
2. The biological dimension of personality in PAIS
targets both sexual activity and the biological sub layer of
aggression [15-17].
3. The psychological dimension research is more
controversial (due to the limits in applying different scales
and standards). Most studies have shown in criminal
subjects (serious offenses of violence and assault) with no
sexual endocrine pathology, a positive correlation between
high testosterone and LH levels and psychological variables
that would express manifest violent behavior [18]. Basal
violent tendencies have not been analyzed and standardized,
and studies which eliminate the differences of opinions
are not enough in order to assess the passive/ dormant
aggressiveness.
4. The sociological dimension is marked by
the biological sub layer through a double mechanism of
feed-before and feed-back. Vasopressin plays a key part
in regulating complex social behaviors such as social
recognition and constructive aggression. Major stress is
discussed both from the perspective of maximum severity
(individual preservation by life or health threat and
species preservation by reproduction threat), and from the
perspective of response to cumulative stress factors, based on
the "untergrunt" - "hintergrunt" relationship model - trigger
stress factor/ key experience and reactive effect through
impulsive/ aggressive behavior. Stress affects personality,
behavior and health, and has cognitive, physiological
and social functioning consequences. Exposure to severe
stress may lead to damage of the amygdala with secondary
dysfunctionality [19,20]. The social and cultural dimension
relates both to a "country" [21] pattern and to the concrete
conditions of the PAIS children's development (educational
level and parental support) [22-24].
The medical status of the two patients is summarized
by a trivalent model approach in table 3.
5. The forensic aspects regarding legal gender
identity. "F" genetically belongs to the male sex, but she
was declared as female and was educated as such. Legally,
in Romania, the sex reassignment surgery is performed
following a forensic and forensic psychiatry expertise at
the request of the court (which has been required to act as
such by the adult patient) in cases of hermaphroditism and
transsexuality (except in cases of pseudohermaphroditism)
as the legal gender must be changed as well. In this case, "F"
requires changing/ correcting the anatomical sex so as to be
aligned with the legal one, so a court order is not necessary.
If hypothetically "F" required the legal gender to match
the genetic gender, considering the above characteristics,
major problems would arise that would require a different
forensic and legal approach which is not yet provided for
in the methodology for sex reassignment surgery (medical
management of a PAIS patient consists in diagnosis as well
as surgical correction as early as possible (before the age
of 18). Theoretically, the two patients are at risk of violent
behavior with possible future forensic consequences (more
severe in "F"). The complex prevention possibilities are
limited because they depend on factors that cannot be legally
imposed. Moreover, in the event of criminally sanctioned
behaviors (possible complication of the pathology), the
defense usually requires a psychiatric forensic expertise
to assess mental competency at the time the offense was
committed. The genetic implications together with the
psychological and social effects of the pathology will lead
to disagreements regardless of the nature/ motivation/ cause
of the crime scene.
6. Ethical aspects. The data presented lead to
the conclusion that patients should be monitored from a
multidisciplinary point of view. If the somatic field shows
no ethical implications, these may occur for preventive
psychiatric monitoring as there are no legal provisions in
this regard. Analyzing the premorbid history and the social
and economic level of patients, it results a low compliance
of the family with the expert advice. Thus both patients
represent cases of undertaken social risk for possible
antisocial behaviors with criminal implications. Assigning
the female gender to "F" cannot be considered a medical
error, as the external genitalia at birth were ambiguous. The
inconsistency between legal gender assigned at birth and
genetic gender involve the well-known long-term health risks
(risks of malignancy, infertility, etc.) as well as the assumed
social risk of inappropriate, possibly criminal, behavior.
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Partial androgen insensitivity syndrome. Multidisciplinary approach
Summarizing, we emphasize that from a surgical
standpoint, the prognosis is good; the success of the surgical
interventions represent the only beneficial somatic, psychological and social factor. The earlier the diagnosis and the surgery take place (initiating surgical treatment in the first 2-3
years of life and continuing specifically into adolescence),
the greater the benefit of surgery is. In the two cases presented, the psychiatric/ psychological/ sociological prognosis is
cautious. Given the controversies in the reference literature
on the forecast correlations between testosterone/ aggression, the fact that in this case the Department of Forensic
Psychiatry of the INML (The National Forensic Institute)
Bucharest carried out clinical and projective psychological
examinations proved to be a beneficial solution in order to
capture the elements of latent (masked / passive) aggression.
Conflict of interest
We declare that there are no ethical conflict of interest.
Abbreviations. AR = androgen receptor; PAIS =
partial androgen insensitivity syndrome; "M" = patient with
legal gender as male; "F" = patient with legal gender as
female; 5-HT = serotonin; NA = noradrenaline; 5-HT1A =
serotonin receptor; LH = luteinizing hormone; FSH = follicle
stimulating hormone; EG = external genitalia.
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